title: Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.
abstract: OBJECTIVE
  Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes.
  
  
  METHODS
  Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993.
  
  
  RESULTS
  Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant.
  
  
  CONCLUSIONS
  Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.
authors.affiliation: Corresponding author: Majken K. Jensen, mkjensen@hsph.harvard.edu.
authors.forename: Majken K
authors.initials: MK
authors.lastname: Jensen
authors.forename: Traci M
authors.initials: TM
authors.lastname: Bartz
authors.forename: Luc
authors.initials: L
authors.lastname: Djoussé
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Kizer
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Zieman
authors.forename: Eric B
authors.initials: EB
authors.lastname: Rimm
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Joachim H
authors.initials: JH
authors.lastname: Ix
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Mukamal
mesh_terms: D001786:Blood Glucose / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics*; D005215:Fasting / Q000097:blood*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D060749:alpha-2-HS-Glycoprotein / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D060749:alpha-2-HS-Glycoprotein